title: 2-Aminoadipic acid is a biomarker for diabetes risk.
abstract: Improvements in metabolite-profiling techniques are providing increased breadth of coverage of the human metabolome and may highlight biomarkers and pathways in common diseases such as diabetes. Using a metabolomics platform that analyzes intermediary organic acids, purines, pyrimidines, and other compounds, we performed a nested case-control study of 188 individuals who developed diabetes and 188 propensity-matched controls from 2,422 normoglycemic participants followed for 12 years in the Framingham Heart Study. The metabolite 2-aminoadipic acid (2-AAA) was most strongly associated with the risk of developing diabetes. Individuals with 2-AAA concentrations in the top quartile had greater than a 4-fold risk of developing diabetes. Levels of 2-AAA were not well correlated with other metabolite biomarkers of diabetes, such as branched chain amino acids and aromatic amino acids, suggesting they report on a distinct pathophysiological pathway. In experimental studies, administration of 2-AAA lowered fasting plasma glucose levels in mice fed both standard chow and high-fat diets. Further, 2-AAA treatment enhanced insulin secretion from a pancreatic β cell line as well as murine and human islets. These data highlight a metabolite not previously associated with diabetes risk that is increased up to 12 years before the onset of overt disease. Our findings suggest that 2-AAA is a marker of diabetes risk and a potential modulator of glucose homeostasis in humans.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Wang
authors.forename: Debby
authors.initials: D
authors.lastname: Ngo
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Psychogios
authors.forename: Andre
authors.initials: A
authors.lastname: Dejam
authors.forename: Martin G
authors.initials: MG
authors.lastname: Larson
authors.forename: Ramachandran S
authors.initials: RS
authors.lastname: Vasan
authors.forename: Anahita
authors.initials: A
authors.lastname: Ghorbani
authors.forename: John
authors.initials: J
authors.lastname: O'Sullivan
authors.forename: Susan
authors.initials: S
authors.lastname: Cheng
authors.forename: Eugene P
authors.initials: EP
authors.lastname: Rhee
authors.forename: Sumita
authors.initials: S
authors.lastname: Sinha
authors.forename: Elizabeth
authors.initials: E
authors.lastname: McCabe
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Fox
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Ho
authors.forename: Jose C
authors.initials: JC
authors.lastname: Florez
authors.forename: Martin
authors.initials: M
authors.lastname: Magnusson
authors.forename: Kerry A
authors.initials: KA
authors.lastname: Pierce
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Souza
authors.forename: Yi
authors.initials: Y
authors.lastname: Yu
authors.forename: Christian
authors.initials: C
authors.lastname: Carter
authors.forename: Peter E
authors.initials: PE
authors.lastname: Light
authors.forename: Olle
authors.initials: O
authors.lastname: Melander
authors.forename: Clary B
authors.initials: CB
authors.lastname: Clish
authors.forename: Robert E
authors.initials: RE
authors.lastname: Gerszten
mesh_terms: D015074:2-Aminoadipic Acid / Q000097:blood*; D000368:Aged; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose; D016022:Case-Control Studies; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000209:etiology; D059305:Diet, High-Fat / Q000009:adverse effects; D005260:Female; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008297:Male; D055442:Metabolome; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009928:Organ Specificity; D015203:Reproducibility of Results; D012306:Risk; D046509:Tissue Culture Techniques
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D007328:Insulin; D015074:2-Aminoadipic Acid